Na1BzoH (6-desoxy-6-benzoylhydrazido-N-allyl-14- hydroxydihydronormorphinone) is a novel opiate active at both mu and kappa receptors. In the presence of Mg++ ions, 3H-NalBzoH labels mu receptors pseudoirreversibly, with a remarkably prolonged rate of dissociation which is 145-fold slower than 3H-naloxone. The binding is not covalent since the GTP analog Gpp(NH)p rapidly dissociates the ligand, presumably by interrupting a stabilized receptor-G-protein complex. 3H-NalBzoH also labels a novel kappa receptor subtype present in high densities in calf, rat and mouse brains, kappa3. In vivo, NalBzoH is a potent, long-acting mu antagonist, blocking morphine analgesia for over 24 hr after a single dose. Low doses of NalBzoH also partially reverse the inhibition of GI transit produced by morphine, completely antagonize morphine lethality and precipitate withdrawal in morphine-dependent mice. Higher NalBzoH doses produce analgesia through a kappa receptor mechanism based upon its sensitivity towards a series of antagonists. NalBzoH has excellent oral activity, with a potency equivalent to the subcutaneous route. Thus, NalBzoH has several potential advantages over traditional opiates and could be useful as either a long-acting antagonist or a nonabusable analgesic. We propose to examine the features which distinguish NalBzoH from traditional opiates: 1) its prolonged duration of mu receptor antagonism, 2) its potent kappa analgesia and 3) its excellent oral potency. We will determine whether the prolonged mu receptor antagonism results from pharmacokinetic factors, such as a slow clearance, or whether it corresponds to its ability to label mu receptors pseudoirreversibily. We will determine half-lives of distribution and elimination, volumes of distribution and clearances. Efforts will be made to identify active major metabolites. Using 3H-NalBzoH, we also will investigate the formation of psuedoirreversible mu binding following NalBzoH administration in vivo. We will synthesize a series of analogs of NalBzoH to be examined in binding studies looking at their ability to label mu receptors pseudoirreversibly and their affinity at a variety of opiate receptor subtypes, especially kappa3. Selected derivatives will be synthesized in radiolabeled form and their binding directly examined. Additional derivatives will be examined in vivo. Finally, we will compare the metabolism and pharmacokinetics of NalBzoH following both oral and intravenous administration.